The Norwegian College of Fishery Science, University of Tromsø, N-9037 Tromsø, Norway.
Fish Shellfish Immunol. 2013 Oct;35(4):1079-85. doi: 10.1016/j.fsi.2013.07.014. Epub 2013 Jul 17.
The Mitogen-activated protein kinases (MAPK) are involved in transmitting intracellular signals downstream of diverse cell surface receptors and mediate the response to ligands such as growth factors, hormones and cytokines. In addition, MAPK are critically involved in the innate immune response to pathogen-derived substances, commonly referred to as pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS) and bacterial DNA rich in CpG dinucleotides. Currently, a great deal of knowledge is available about the involvement of MAPK in the innate immune response to PAMPs in mammals; however, little is known about the role of the different MAPK classes in the immune response to PAMPs in lower vertebrates. In the current study, p38 phosphorylation was induced by CpG oligonucleotides (ODNs) and LPS in primary salmon mononuclear phagocytes. Pre-treatment of the cells with a p38 inhibitor (SB203580) blocked the PAMP-induced p38 activity and suppressed the upregulation of most of the CpG- and LPS-induced transcripts highlighting the role of this kinase in the salmon innate immune response to PAMPs. In contrast to p38, the phosphorylation of extracellular signal-regulated kinase (ERK), a MAPK involved primarily in response to mitogens, was high in resting cells and, surprisingly, incubation with both CpG and control ODNs downregulated the phospho-ERK levels independently of p38 activation. The basal phospho-ERK level and the CpG-inducible p38 phosphorylation were greatly influenced by the length of in vitro incubation. The basal phospho-ERK level increased gradually throughout a 5-day culture period and was PI3K-dependent as demonstrated by its sensitivity to Wortmannin suggesting it is influenced by growth factors. Overall these data indicate that both basal and PAMP-induced activity of MAPKs might be greatly influenced by the differentiation status of salmon mononuclear phagocytes.
丝裂原活化蛋白激酶（MAPK）参与细胞表面受体下游的多种细胞内信号转导，并介导对配体（如生长因子、激素和细胞因子）的反应。此外，MAPK 还参与对病原体来源物质（通常称为病原体相关分子模式（PAMP））的固有免疫反应，例如细菌脂多糖（LPS）和富含 CpG 二核苷酸的细菌 DNA。目前，人们对 MAPK 参与哺乳动物对 PAMP 的固有免疫反应有了大量的了解；然而，对于不同 MAPK 类在脊椎动物对 PAMP 的免疫反应中的作用知之甚少。在本研究中，CpG 寡核苷酸（ODN）和 LPS 在鲑鱼单核吞噬细胞中诱导 p38 磷酸化。用 p38 抑制剂（SB203580）预处理细胞可阻断 PAMP 诱导的 p38 活性，并抑制大多数 CpG 和 LPS 诱导的转录物的上调，突出了该激酶在鲑鱼对 PAMP 的固有免疫反应中的作用。与 p38 不同，细胞外信号调节激酶（ERK）的磷酸化，一种主要参与有丝分裂原反应的 MAPK，在静止细胞中水平较高，令人惊讶的是，与 CpG 和对照 ODN 孵育均可独立于 p38 激活下调磷酸化 ERK 水平。基础磷酸化 ERK 水平和 CpG 诱导的 p38 磷酸化受体外孵育时间的长短影响很大。基础磷酸化 ERK 水平在 5 天的培养期间逐渐升高，并且依赖于 PI3K，其对 Wortmannin 的敏感性表明它受生长因子的影响。总体而言，这些数据表明，MAPK 的基础和 PAMP 诱导活性可能受鲑鱼单核吞噬细胞分化状态的极大影响。
